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Cytokines are critical mediators in autoimmunity and a better understanding of their mode of action should contribute to the development of strategies for controlling harmful autoimmune reactions. Their complicated nature makes it difficult to classify them as pro- or anti-inflammatory mediators; redundancy in their mode of action has been widely reported. Their complexity is further exemplified by the fact that several cytokines display redundancy in their receptor usage, with the recently identified IL-12 and IL-10 families being prototypical examples. Several aspects--including kinetics of expression, mode of induction, regulation of receptor expression and competition for occupancy, and the stage (acute vs chronic) of the disease--are critical to the net effect, and all these aspects need to be understood if we are to define a cytokine's whole nature.

Cytokines are the co-ordinators of the immune system and, as such, are important targets for immunomodulation. Progress has been made towards the use of IL-10 for immunosuppressive therapy to prevent autoimmunity. Interest has also recently focused on the role of cytokines in controlling the activation of dendritic cells and NK cells, and the consequences of this for the development of autoaggressive responses. Genes involved in IFN-activated pathways that control the survival of lymphocytes have been strongly linked to lupus susceptibility, and IFN-mediated defenses against viral infection have been shown to determine susceptibility to a model of viral-induced diabetes.

Autoimmune responses are controlled by complex regulatory circuits. Previous work has revealed that factors controlling autoimmunity can act both as potentiating and inhibitory agents, depending upon the site and timing of exposure. Recent advances in this complex field have at least partially uncovered the mechanism whereby these regulatory molecules participate in autoimmune processes. IL-12 production in the absence of infection may predispose to autoimmunity. IL-4 and transforming growth factor beta may suppress autoreactive T cells. Proinflammatory cytokines may ameliorate autoimmunity, dependent on the timing and level of production. In many cases, cytokines may act via antigen-presenting cells.

The past year has seen advances in our understanding of the mechanisms that control the expression of organ-specific autoimmunity. Attempts to develop therapeutic strategies for the prevention of autoimmune disease have largely been based on deviation of the T-cell response away from an autoaggressive, pro-inflammatory Th1 response. Manipulation of the cytokine environment at the site of antigen uptake or presentation, the source of endogenous antigen, costimulatory molecules or peptides processed and presented has yielded interesting results.

Transgenic and knockout mice have been valuable tools for clarifying the roles of individual cell types and effector molecules in the pathogenesis of autoimmunity. During the past year, new strains have been added to the large array of transgenic mice, with broad or tissue-specific expression of transgene products. These laboratory models, as well as knockout mice lacking genes for a particular molecule, have greatly enhanced our understanding of autoimmune disease.

The ability of transgenic mice to express a specific protein in a specific tissue has enabled the mechanisms of self-tolerance and autoimmunity to be elucidated. Further studies, combined with more sophisticated methods of gene targeting, will provide insights into the pathway leading from loss of self-tolerance to autoimmunity.